The principal goal of this research is to develop antigen-specific immunotherapy for an autoimmune disease of skeletal muscle, myasthenia gravis (MG). Related goals are the definition of genetic factors influencing susceptibility to MG, and the immunologic mechanisms involved in effecting and suppressing the disease process. Antigenic determinants of nicotinic acetylcholine receptors (AChR) that are involved in the pathogenesis of MG will be defined using monoclonal antibodies. Antibodies produced by B-lymphocytes from MG patients hybridized with a suitable myeloma line should give direct information about determinants of AChR that are relevant to the pathogenesis of MG. The role of the thymus in MG will be a focus of our investigations, particularly the role of non-lymphoid thymic elements. The antigenicity of AChR in non-innervated muscle (such as is found in the thymus, the putative site where MG is initiated) will be compared with that of innervated muscle, and the antigenicity of thymus and oculobulbar muscle AChR (of putative neuroectodermal origin) will be compared with that of AChR in limbs (of mesodermal origin). The association between thymoma and autoimmunity to AChR will be investigated, both in patients with MG and in the thymoma-prone AKR/J strain of mouse, which has anomalous immune responsiveness to AChR.